Verapmil therapy

ABSTRACT

A dosage form is disclosed comprising means for delaying the delivery of drug from the dosage form following the administration of the dosage form to a patient in need of drug therapy.

DISCLOSURE OF TECHNICAL FIELD

This invention pertains to a novel dosage form useful for delayed-drugdelivery. More specifically, the invention relates to a dosage form thatafter administration of the dosage form is followed by a drug-freeperiod, which dosage form at this later time delivers a dose of drug fordelayed therapy. The drug is delivered during the drug-delivery periodat a controlled rate over time. The invention concerns also a method ofdelayed-drug therapy by administering a dosage form that delays theonset of drug delivery, and after the drug-free interval delivers a drugfor its therapeutic effect.

DISCLOSURE OF BACKGROUND ART

A critical need exists for a dosage form that makes available at a latertime a drug to satisfy a therapeutic demand. The demand can arise duringa circadian or chronological cycle, or the demand can arise forproducing a therapeutic effect a later time, such as during the morninghours. For examples, many patients with myocardial infarction exhibit aclinical incidence of this syndrome that shows a circadian distributionwith high frequency in the morning hours between 4:00 a.m. and 9:00a.m., as reported in The American Journal of Cardiology, Vol. 62, pages635 to 637, 1988; Circulation, Vol. 82, pages 897 to 902, 1990; andHeart Disease, Vol. 2, pages 1234 to 1235, 1988. Yet, the medical art,previously lacked a dosage form for administering a drug that providestherapy for this application during these critical hours.

There are dosage forms known to the prior art for delivering a drugcontinuously over time, such as disclosed in U.S. Pat. No. 4,327,725issued to Cortese and Theeuwes, and in U.S. Pat. Nos. 4,612,008;4,765,989; and 4,783,337 issued to Wong, Barclay, Deters and Theeuwes.The dosage forms disclosed in these patents comprise a semipermeablewall that surrounds a compartment. The compartment comprises a drugformulation, and in contact with the drug formulation, a displacementmember that pushes the drug formulation from the dosage form. Thesedosage forms operate by imbibing fluid through the semipermeable wallinto the compartment, wherein the fluid contacts and motivates thedisplacement member to consume space and thereby pushes the drugformulation from the dosage form. These dosage forms operatesuccessfully for their intended use, and they can deliver many difficultto deliver drugs for their intended purpose. One limitation, however,associated with these dosage forms, consists in the dosage formimmediate delivery of drug to a drug recipient. That is, the dosageforms do not provide for the delayed delivery of a drug to satisfy afuture therapeutic need.

It is immediately apparent in the light of the above presentation that apressing need exists for a dosage form that can delay the delivery of adrug to provide a drug-free interval and then deliver a dose of drug. Itwill be appreciated by those versed in the dispensing art, that if anovel and unique dosage form is made available for executing atherapeutic program comprising a drug-free interval followed by adrug-delivery interval, such a delayed drug-delivery dosage form wouldhave a practical application, and it would also represent a valuablecontribution to the medical arts.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide a novel and useful dosage form thatrepresents an unexpected improvement in the dispensing art andsubstantially overcomes the disadvantages known to the prior art.

Another object of the present invention is to provide a dosage form thatcan delay the delivery of a beneficial drug.

Another object of the present invention is to provide a dosage form thatcan delay the delivery of the drug from the dosage form, and thendeliver a dose of the drug.

Another object of the present invention is to provide a novel dosageform comprising means for delaying the delivery of drug, followed bymeans for delivering at a later time a dose of drug.

Another object of the present invention is to provide a novel dosageform comprising means for delaying the delivery of drug for 30 minutesup to 4.5 hours from a dosage form.

Another object of the present invention is to provide a novel dosageform that overcomes the limited functionality of conventional dosagetablets, and which novel dosage form can perform a drug programcomprising a drug-free period for a duration as needed, and then toprovide a drug-delivery period as needed for a time to achieve a desiredtherapeutic program.

Another object of the invention is to provide a dosage form comprisingin a single dosage form a dosage of drug that is released by the dosageform at least two hours after the dosage form is administered to a drugrecipient, and then delivers a drug for a later therapeutic effect.

Another object of the present invention is to provide a novel dosageform manufactured in the form of a drug delivery device comprising meansfor providing a drug-free interval, and means for then providing afuture dose of drug.

Another object of the present invention is to provide a novel dosageform that makes available at a later time a drug for satisfying a needthat can arise during a circadian or chronological cycle, or forproviding a drug during the morning hours.

Another object of the invention is to provide a therapeutic programcomprising an instant dose of drug, followed by a drug-free interval andthen a drug-delivery interval.

Other objects, features and advantages of the invention will be moreapparent to those versed in the dispensing art from the followingspecification, taken in conjunction with the drawing figures and theaccompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

Drawing FIG. 1 is a general view of a dosage form provided by theinvention, which dosage form is designed and shaped for oraladministration, and for a delayed pattern of drug delivery to thegastrointestinal tract;

Drawing FIG. 2 is an opened view of the dosage form of FIG. 1 fordepicting the structure of the dosage form, wherein the wall of thedosage form comprises means for delaying the delivery of drug from thedosage form;

Drawing FIG. 3 is an opened view of the dosage form of FIG. 1, fordepicting the internal structure of the dosage form, wherein the dosageform comprises an internal coat for delaying drug delivery, which coatsurrounds a drug reservoir for delaying the delivery of drug from thereservoir of the dosage form;

Drawing FIG. 4 is an opened view of the dosage form of FIG. 1,comprising external means for delivering an immediate pulsed dose ofdrug followed by a drug-free interval and then a drug-delivery intervalfor a therapeutic effect; and,

Drawing FIG. 5 depicts the change in viscosity for a polymer in responseto fluid stress of increasing concentrations.

In the drawing figures and in the specification, like parts in relatedfigures are identified by like numbers. The terms appearing earlier inthe specification and in the description of the drawing figures, as wellas embodiments thereof, are further described elsewhere in thedisclosure.

DETAILED DESCRIPTION OF THE DRAWING FIGURES

Turning now to the drawing figures in detail, which drawing figures areexamples of dosage forms provided by the invention, and which examplesare not to be construed as limiting, one example of a dosage form isseen in drawing FIG. 1. In drawing FIG. 1, a dosage form 10 is seencomprising a body member 11 comprising a wall 12, that surrounds aninternal structure not seen in drawing FIG. 1. Dosage form 10 comprisesat least one exit port 13 for connecting the exterior with the interiorof dosage form 10.

In drawing FIG. 2, dosage form 10 of FIG. 1 is seen in opened section.In drawing FIG. 2, dosage form 10 comprises a body 11, a wall 12 thatsurrounds and forms internal compartment 14, that communicates through apassageway 13 with the exterior of the dosage form 10. Wall 12 comprisesa semipermeable composition and it comprises wall forming means 15 fordelaying the delivery of drug 16 from compartment 14. Compartment 14contains a drug composition 16 comprising drug 16 and polymeric means 17for delaying the delivery of drug 16. Polymeric means 17 possesses aslow rate of hydration dependent on its high molecular weight andviscosity. The slow rate of hydration of internal polymeric means 17provides a corresponding slow rate of imbibition of fluid through wall12, to change the viscosity of means 17 from an essentiallynon-dispensable phase to a dispensable phase thereby providing a delayeddrug delivery followed by a drug-delivery period. Polymeric means 17operates in conjunction with wall-forming polymeric composition 15 inwall 12. The polymeric composition 15 in wall 12 possesses a slow rateof fluid hydration and this further slows the rate of fluid imbibitionby internal polymeric means 17 by restricting fluid to polymeric means17 and consequently its change in viscosity. The slow rate of hydrationin wall 12 generally is from 15 minutes to 3 hours and in a presentlypreferred manufacture for 15 minutes to 2 hours. The combined operationof internal polymeric means 17 and wall-polymeric composition 15produces a delayed-drug interval of at least two hours, or more.

Compartment 14 also houses a second or an osmotic composition 18 that isdistant from passageway 13 and in contacting relation with the first ordrug 16 composition. The second composition 18 contributes a drivingforce that acts in cooperation with the first or drug 16 composition fordelivering the preferred therapeutic amount of drug 16 during the drugdelivery interval from dosage form 10. The second composition 18comprises an optional osmagent 19 represented by dash lines, that issoluble in fluid imbibed into compartment 14, and they exhibit anosmotic pressure gradient across semipermeable wall 12 against anexternal fluid. The osmagent in another manufacture is blended with anosmopolymer 20, which osmopolymer 20 imbibes fluid into compartment 14and it exhibits an osmotic pressure gradient across semipermeable wall12 against an external fluid. The osmopolymer 20 and osmagent 19 arehydrophilic water-loving osmotically effective agents, and they possessosmotic properties such as the ability to imbibe external fluid throughsemipermeable wall 12. They exhibit an osmotic pressure gradient acrossthe semipermeable wall against the external fluid, and they occupy spacefor pushing the drug composition by space displacement through exitports 13. The osmagent 19 is preferably mixed with osmopolymer 20 forimbibing the optimal maximum volume of external fluid into compartment14. The imbibed fluid is available to optimize the volumetric rate andfor expansion of the second composition.

Drawing FIG. 3 illustrates another manufacture provide by the invention.Drawing FIG. 3 depicts dosage form 10 comprising body 11, wall 12comprising chemical means 15 for slowing the rate of fluid imbibitionthrough wall 12 into compartment 14, drug 16 in compartment 14,polymeric viscosity governing means 17 in compartment 14, and secondcomposition 18, which composition 18 comprises at least one of a memberselected from the group consisting of osmagent 19 and osmopolymer 20.Dosage form 10, in drawing FIG. 3, comprises a layer 21 that surroundsthe drug 16 composition and the osmotic 18 composition. Layer 21 ispositioned between the inside of wall 12 and the drug 16 composition andthe osmotic 18 composition. Layer 21 comprises a polymer that possessesa resistance to take-up water, and it slows or delays the rate of fluidimbibition into compartment 14. The physics-chemical action of layer 21thereby contributes to the delayed-delivery of drug 16 from dosage form10.

Drawing FIG. 4 illustrates another manufacture provided by the presentinvention. In drawing FIG. 4, dosage form 10 comprises an exterior coat22 that comprises a dosage unit amount of drug 16 for an initial pulsedose of drug 16 prior to a drug-free interval. The initial pulse is afirst dose of drug 16 followed by a drug-free interval, which latterinterval is followed by a drug-delivery interval. Exterior coat 22comprises from about 0.1 to 99.9 weight percent (wt %) of a drug, andfrom 99.9 to 0.1 wt % of a pharmaceutically acceptable carrier for thedrug. The total weight percent of all the coat-forming ingredient isequal to 100 wt %. In a more preferred embodiment the initial pulse doseof drug 16 is from 5 to 75 wt % and from 95 to 25 wt % of thepharmaceutically acceptable carrier. The carrier is a means for coatingthe drug onto the exterior surface of wall 12. In a fluid environment ofuse, the carrier releases the drug 16 thereby providing the initial orpulsed dose of drug. The coat 22 releases the initial pulsed dose infrom greater than zero time, usually 2.5 minutes up to 1 hour, and in apresently preferred pulsed dose time of from several minutes, morespecifically from 5 minutes, up to 30 minutes.

The dosage form 10 of drawing FIGS. 1 through 4 can be used fordelivering drugs for their therapeutic benefit. The dosage forms 10 cantake a wide variety of shapes, sizes and forms adapted for delivering adrug to the environment of use. For example, the dosage forms includeoral, buccal, sublingual, intrauterine, vaginal, anal-rectal andartificial glands dosage forms.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of this invention it has now been foundthat a dosage form 10 can be manufactured with a first composition and adifferent second composition mutually housed in cooperative relationshipin the compartment of the dosage form. The dosage form comprises a wallthat defines a compartment. The wall comprises a material that does notadversely affect the beneficial drug, osmagent, osmopolymer, and thelike. The wall is permeable, that is the wall is permeable to thepassage of an external fluid such as water and biological fluids, and itis substantially impermeable to the passage of drugs, osmagents,osmopolymers, and the like. The wall comprises a material that does notadversely affect an animal, or host, or the components comprising thedosage form, and the selectively semipermeable materials used forforming the wall are nonerodible and they are insoluble in fluids.Typical materials for forming the wall are, in one embodiment, celluloseesters, cellulose ethers and cellulose ester-ethers. These cellulosicpolymers have a degree of substitution, D.S., on the anhydroglucoseunit, from greater than 0 up to 3 inclusive. By degree of substitutionis meant the average number of hydroxyl groups originally present on theanhydroglucose unit comprising the cellulose polymer that are replacedby a substituting group. Representative materials include a memberselected from the group consisting of cellulose acylate, and cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetate,cellulose triacetate, mono-, di-, and tricellulose alkanylates, mono-,di-, and tricellulose aroylates, and the like. Exemplary polymersinclude cellulose acetate having a D.S. up to 1 and an acetyl content upto 21%; cellulose acetate having an acetyl content of 32 to 39.8%;cellulose acetate having a D.S. of 1 to 2 and an acetyl content of 21 to35%; cellulose acetate having a D.S. of 2 to 3 and an acetyl content of35 to 44.8%, and the like. More specific cellulosic polymers includecellulose propionate having a D.S. of 1.8 and a propyl content of 39.2to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyratehaving a D.S. of 1.8, an acetyl content of 13 to 15% and a butyrylcontent of 34 to 39%; cellulose acetate butyrate having an acetylcontent of 2 to 29%, a butyryl content of 17 to 53% and a hydroxylcontent of 0.5 to 4.7%; cellulose triacylates having a D.S. of 2.9 to 3, such as cellulose trivalerate, cellulose trilaurate, cellulosetripalmitate, cellulose trisuccinate, and cellulose trioctanoate;cellulose diacylates having a D.S. of 2.2 to 2.6, such as cellulosedisuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulosedipentanoate, co-esters of cellulose, such as cellulose acetate butyrateand cellulose acetate propionate.

Additional polymers include ethyl cellulose of various degree ofetherification with ethoxy content of from 40 to 55%, acetaldehydedimethylcellulose acetate, cellulose acetate ethyl carbamate, celluloseacetate methyl carbamate, cellulose acetate diethyl aminoacetate,semipermeable polyamides; semipermeable polyurethanes; semipermeablesulfonated polystyrenes; semipermeable cross-linked selective polymersformed by the coprecipitation of a polyanion and a polycation asdisclosed in U.S. Pat. Nos. 3,173,876; 3,276,586; 4,541,005; 3,541,006,and 3,546,142; semipermeable polymers as disclosed by Loeb andSourirajan in U.S. Pat. No. 3,133,132; semipermeable lightlycross-linked polystyrene derivatives; semipermeable cross-linkedpoly(-sodium styrene sulfonate); semipermeable cross-linkedpoly(vinylbenzyltrimethyl ammonium chloride); semipermeable polymersexhibiting a fluid permeability of 2.5×10⁻⁸ to 2.5×10⁻⁴ (cm² /hr.atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross the semipermeable wall. The polymers are known to the art in U.S.Pat. Nos. 3,845,770; 3,916,899; and 4,160,020; and in Handbook of CommonPlymers, by Scott, J. R. and Roff, W. J., 1971, published by CRC Press,Cleveland, Ohio.

The polymeric composition 15 present in wall 12 for slowing or fordelaying the passage of a fluid, such as water or a biological fluidthrough wall 12 comprises a polymer exhibiting a 8,500 to 1,000,000molecular weight, and present in wall 12 in a concentration of 35 wt %to 55 wt %. Polymeric materials operable for the present purposeconsists of a member selected from the group consisting ofhydroxypropylcellulose, phenylcellulose, benzylcellulose,benzhydrylcellulose, diphenylmethylcellulose and tritylcellulose.

Carrier member 22 used for containing exterior drug 16 in drug-releasingrelation, which carrier member 22 is positioned on the exterior surfaceof wall 12 comprises a member selected from the group consisting ofhydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxybutylcellulose, hydroxypentylcellulose,hydroxypropylmethylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose. Carrier22, when present, is from 0.1 mm to 10 mm thick, for providing a dose ofdrug.

Layer 21 in initial contacting relation with the internal surface ofsemipermeable wall 12 and in initial contacting relation with drug 16composition and with push 18 composition, comprises a layer 21, 0.1 mmto 15 mm thick. Layer 21 comprises a member selected from the groupconsisting essentially of hydroxypropylcellulose,hydroxyphenylcellulose, phenylcellulose, benzylcellulose,benzhydrylcellulose, diphenylmethylcellulose and tritylcellulose. Thecellulosic polymer comprising layer 21 can be the same or different thanthe cellulosic polymer 15 present in wall 12.

In the specification and the accompanying claims, the term "drug 16"includes any physiologically or pharmacologically active substance thatproduces a local or systemic effect, in animals, including warm-bloodedmammals, humans and primates; avians; household, sport and farm animals;laboratory animals; fishes; reptiles and zoo animals. The term"physiologically", as used herein, denote the administration of drug 16to produce generally normal levels and functions. The term"pharmacologically" denotes generally variations in response to theamount of drug administered to the host. See Stedman's MedicalDictionary, 1966, published by Williams and Wilkins, Baltimore, MD. Theterm "circadian", as used herein, denotes a biological activity thatrecurs at intervals during a 24 hour period. The phrase "drugformulation", as used herein, means the drug is in the compartment mixedwith means for delaying the delivery of drug 16 from dosage form 10. Thedrug 16 that can be delivered includes inorganic and organic drugswithout limitation includes drugs that act on the peripheral nerves,adrenergic receptors, cholinergic receptors, nervous system, skeletalmuscles, cardiovascular system, smooth muscles, blood circulatorysystem, synaptic sites, neuro-effector junctional sites, endocrinesystem, hormone systems, immunological system, reproductive system,skeletal system, autacoid systems, alimentary and excretory systems,inhibitory of autocoid systems, inhibitory of histamine systems. Theactive drug that can be delivered for acting on these recipients includeanticonvulsants, analgesics, antiparkinsons, anti-inflammatories,calcium antagonists, anesthetics, antimicrobials, antimalarials,antiparasites, antihypertensives, antihistamines, antipyretics,alpha-adrenergic agonist, alpha-blockers, biocides, bactericides,bronchial dilators, beta-adrenergic blocking drugs, contraceptives,cardiovascular drugs, calcium channel inhibitors, depressants,diagnostics, diuretics, electrolytes, hypnotics, hormonals,hyperglycemics, muscle contractants, muscle relaxants, ophthalmics,psychic energizers, parasympathomimetics, sedatives, sympathomimetics,tranquilizers, urinary tract drugs, vaginal drugs, vitamins,nonsteroidal anti-inflammatory drugs, angiotensin converting enzymes,polypeptide drugs, and the like.

Drug 16, that can be dispensed by dosage form 10, is represented by acalcium channel blocker such as nifedipine, isradipine, nilvadipine,verapamil, flunarizine, nimodipine, diltiazem, nicardipine,norverapamil, nitredipine, nisoldipine, felodipine, amlodipine,cinnarizine and fendiline. Drug 16, that also can be dispensed by dosageform 10, is represented by an angiotensin converting enzyme inhibitorselected from the group consisting of angiotensin converting enzymeinhibitors that are essentially-free of sulfur, angiotensin convertingenzyme inhibitors containing a sulfhydryl group, angiotensin convertingenzyme inhibitors containing a linear sulfide, angiotensin convertingenzyme inhibitors containing a cyclic sulfide, and angiotensinconverting enzyme inhibitors containing a methylsulfonyl group.Representation of angiotensin converting enzyme inhibitors are morespecifically represented by a member selected from the group consistingof ramipril, fosinopril, altiopril, benazepril, libenzapril, alacepril,cilazapril, cilazaprilat, perindopril, zofenopril, enalapril,lisinopril, imidapril, spirapril, rentiapril, captopril, delapril,alindapril, indalapril, and quinapril. The amount of beneficial drug ina dosage form generally is about from 0.05 ng to 1.5 g or more, withindividual dosage forms containing, for example, 25 ng, 1 mg, 5 mg, 10mg, 25 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.0 g or 1.2 g. Thebeneficial drugs are known to the art in Pharmaceutical Sciences, 14thEd., edited by Remington, (1979) published by Mack Publishing Co.,Easton, Pa; The Drug, The Nurse, The Patient, Including Current DrugHandbook, by Falconer, et al.,(1974-1976), published by Saunder Company,Philadelphia, Pa; Medicinal Chemistry, 3rd Ed., Vol. 1 and 2, by Burger,published by Wiley-Interscience, N.Y.; and in Physician's DeskReference, 38 Ed., (1984), published by Medical Economics Co., Oradell,N.J.

The drug can be in various forms, such as uncharged molecules, molecularcomplexes, pharmacologically acceptable salts such as inorganic,organic, hydrochloride, hydrobromide, sulfate, laurate, palmitate,phosphate, nitrite, borate, acetate, maleate, tartrate, oleate andsalicylate. For acidic drugs, salts or metals, amines or organiccations; for example, quaternary ammonium can be used. Derivatives ofdrugs, such as esters, ethers and amides, can be used as represented by,for example, hydroxy, lower alkoxy, lower alkenoxy, diloweralkylaminolower alkoxy (for example, dimethylaminoethoxy), acylamino lower alkoxy(for examples, acetylaminoethoxy), acyloxy lower alkoxy (for example,pivaloyloxyethoxy), aryloxy (for example, phenoxy), aryl lower alkoxy(for example, benzyloxy), amino, lower alkylamino, diloweralkylamino,hydroxyamino, aryllower alkylamino (for example, benzylamino), orsubstituted aryloxy or substituted arylloweralkoxy wherein thesubstituent is methyl, halo or methoxy.

Polymeric viscosity governing means 17 blended with drug 16, is usefulfor producing a delay or drug-free interval, according to the mode andthe manner of the invention. The polymeric means 17 responds, when fluidstress is applied thereto, to a change from a delayed-drug free state toa dispensable drug delivery state. The change is accompanied by thepolymeric means imbibing fluid to increase its viscosity, that is, tochange from a non-fluid to a semifluid or viscous dispensable phase. Thechange can take from 30 minutes up to 4.5 hours, more preferably, from45 minutes up to 3 hours, thereby producing the drug-free delay period.Representative of a polymeric means operable for the purpose of thisinvention are polymers comprising a 250,000 to 1,000,000 molecularweight and possess the ability to imbibe fluid for changing over timefrom a delay to a dispensable state. In a present preferred embodiment,the first composition comprises 20 wt % to 50 wt % of polymeric means17. The polymers in a 2 wt % to 9 wt % concentration in water exhibit aviscosity at 25° C. of 45 to 10,000 cps (centipoises). Morespecifically, the presently preferred embodiment comprises polyethyleneoxide possessing a 250,000 to 350,000 molecular weight and a 600 to1,200 viscosity range for a 5% solution at 25° C., cps. The viscosityrange for a polymer comprising a 300,000 molecular weight that imbibesan aqueous fluid is seen in accompanying drawing FIG. 5. The polymericmeans 17 inside compartment 14 operates in conjunction with polymer 15in wall 12. Polymer 15 by slowing the fluid flux into compartment 14,limits the volume of aqueous or biological fluid available to polymer17, thereby concomitantly contributing to the delay interval provided bypolymer 17. Polymer 15 and polymer 17 operate together in concert toprovide a delay of 2 to 4.5 hours for dosage form 10. Viscositymeasurements can be made according to the procedures described inChemical Dictionary, Fifth Ed., by Grant, page 621, (1987), published byMcGraw Hill Inc.; Encyclopedia of Chemistry , Fourth Edition, pages 822to 826, (1984), published by Van Nostrand Reinhold Inc.; and inPharmaceutical Sciences, by Remington, 17th Edition, pages 330 to 345,(1985), published by Mack Publishing Co.

The drug composition comprising drug 16 and polymeric means 17optionally comprises from 0 to 20 wt % of an osmagent. The osmagent areknown also as osmotically effective solutes, they are soluble in fluidthat enters dosage form 10, and they exhibit an osmotic pressuregradient across semipermeable wall 12 against an exterior fluid.Representative of an osmagent, as seen in drawing FIG. 2, as circle 23,comprise a member selected from the group consisting of magnesiumsulfate, magnesium chloride, sodium chloride, lithium chloride,potassium sulfate, sodium sulfate, lithium sulfate and sodium sulfate.The drug composition comprises an optional binder 24, seen in drawingFIG. 2, as a vertical line. The concentration of binder 24 is from 0 wt% to 20 wt %, more preferably from 0 wt % to 10 wt %. Representative ofa specific binder for holding the drug composition in core formation, ispolyvinylpyrrolidone having a molecular weight of 35,000 to 45,000,usually 38,000 to 40,000. The drug composition comprises 0 wt % to 3.5wt % of a lubricant, such as magnesium stearate, calcium stearate orstearic acid.

Osmotic composition 18, the second composition comprises an osmopolymer20. The osmopolymer exhibits fluid absorbing and/or fluid imbibingproperties. The osmopolymer comprises a hydrophilic polymer that caninteract with water and aqueous fluids and swell or expand to anequilibrium state. The osmopolymer exhibits the ability to retain asignificant portion of the imbibed or absorbed fluid. In operation, thedrug composition and the osmotic composition cooperate to deliver thedrug 16 from dosage form 10. In operation, the osmotic compositionabsorbs fluid, expands and exerts pressure against the drug composition.The osmopolymers swell or expand to a very high degree, usually to a 2to 50 fold increase in volume. Representative of osmopolymers consistsof a member selected from the group consisting of poly(hydroxyalkylmethacrylate) having a molecular weight of 20,000 to 5,000,000;poly(vinylpyrrolidone) having a molecular weight of about 10,000 to360,000; poly(vinyl alcohol) having a low acetate content and lightlycross-linked with glyoxal, formaldehyde, glutaraldehyde and having adegree of polymerization from 2,000 to 30,000; poly(ethylene oxide)having a molecular weight from 10,000 to 7,800,000; acidic carboxypolymers known as carboxypolymethylene or as carboxyvinyl polymers, apolymer consisting of acrylic acid lightly cross-linked withpolyallylsucrose and sold under the trademark Carbopol®, acidic carboxypolymer having a molecular weight of 200,000 to 6,000,000, includingsodium acidic carboxyvinyl hydrogel and potassium acidic carboxyvinylhydrogel; Cyanamer® polyacrylamide; and the like. The representativepolymers are known to the art in Handbook of Common Polymers, by Scottand Roff, published by the Chemical Company, Cleveland, Ohio; ACSSymposium Series, No. 31, by Ratner and Hoffman, pp. 1 to 36, (1976),published by the American Council Society; and in Recent Advances inDrug Delivery Systems, by Schacht, pp. 259 to 278, published by PlenumPress, N.Y. The concentration of osmopolymer present in the osmoticcomposition is from 60 wt % to 85 wt %. The osmotic compositioncomprises from 2 wt % to 15 wt % of a hydroxypropylalkylcellulosepossessing a 9,000 to 25,000 molecular weight and consisting of a memberselected from the group consisting of hydroxypropylmethylcellulose,hydroxypropylethylcellulose, hydroxypropylbutylcellulose andhydroxypropylpentylcellulose. The osmotic composition optionallycomprises 0.01 to 3.5 wt % of a lubricant, from 0.20 wt % to 2.0 wt % offerric oxide, and from 15 wt % to 30 wt % of an osmagent. The totalweight percent of all ingredients in the osmotic composition is equal to100 wt %. Osmotically effective osmagents useful for the present purposeinclude magnesium sulfate, magnesium chloride, sodium chloride, lithiumchloride, potassium sulfate, sodium sulfate, sodium carbonate, lithiumsulfate, sodium sulfate, and the like. The osmagent is usually presentas a particle, powder, granule, or the like. The osmotic pressure inatmospheres, ATM, of the osmagent suitable for the invention will begreater than zero ATM, generally from zero ATM up to 500 ATM, or higher.The osmotic pressure of an osmagent is measured in a commerciallyavailable osmometer that measures the vapor pressure difference betweenpure water and the solution to be analyzed, and according to standardthermodynamic principles the vapor pressure ratio is converted into anosmotic pressure difference. The osmometer used from the presentmeasurements is identified as Model 1001-A Vapor Pressure Osmometer,manufactured by Knauer and distributed by Utopia Instrument Co., Joliet,Ill.

The expression "exit means 13" as used herein comprises means andmethods suitable for releasing drug from compartment 14. The expressionincludes at least one passageway or orifice that passes through wall 12for communicating with compartment 14. The expression "at least onepassageway" includes aperture, orifice, bore, pore, porous elementthrough which drug can migrate, a hollow fiber, capillary tube and thelike. The expression includes also a material that erodes or is leachedfrom wall 12 in the fluid environment of use to produce at least onepassageway in the dosage form. Representative materials suitable forforming at least one passageway, or a multiplicity of passagewaysinclude an erodible polycarbonate, poly(glycolic), or poly(lactic) acidmember in the wall, a gelatinous filament, leachable materials such asfluid removable pore forming polysaccharides, salts or oxides, and thelike. A passageway or a plurality of passageways can be formed byleaching a material such as sorbitol from the wall to produce acontrolled release pore-passageway. The passageway can have any shape,such as round, triangular, elliptical, and the like. The dosage form canbe constructed with one or more passageways in spaced apart relation onmore than a single surface of a dosage form. Passageways and equipmentfor forming passageways are disclosed in U.S. Pat. Nos. 3,916,899;4,063,064; and 4,088,864. Pore-passageways of controlled dimensionsformed by leaching are disclosed in U.S. Pat. No. 4,200,098.

The wall 12 of the dosage form 10 and the exterior coat 22 can be formedin one technique using the air suspension procedure. This procedureconsists in suspending and tumbling delayed, bilayer compositions in acurrent of air and a wall forming or outer coat composition, until ineither operation the wall or the coat is applied to the delayed bilayercompositions. The air suspension procedure is well-suited forindependently forming the wall of the dosage form. The air suspensionprocedure is described in U.S. Pat. No. 2,799,241; in J. Am. Pharm.Assoc., Vol. 48, pp. 451 to 459, (1959); and, ibid, Vol. 49, pp. 82 to84, (1960). The osmotic systems can also be coated with the wall formingcomposition, or the composition with a Wurster® air suspension coater,using for example, methylene dichloride--methanol cosolvent. TheAeromatic® air suspension coater can be used also employing a cosolvent.Other coating techniques, such as pan coating, can be used for providingthe wall of the dosage form. In the pan coating system the wall 12forming, or the exterior coat 22 are deposited by successive spraying ofthe composition on the delayed compositions, accompanied by tumbling ina rotating pan. A pan coater is used because of its availability atcommercial scale. An interposed layer, or an external coat can beapplied by press coating during the manufacture of the dosage form.Finally, the wall or coated dosage form are dried in a forced air ovenat 40° C. for a week, or in a temperature and humidity controlled ovenfor 24 hours at 40° C. and 50% relative humidity, to free the dosageform of solvent. Generally, the wall formed by these techniques has athickness of 2 to 20 mils with a presently preferred thickness of 4 to10 mils. The exterior coated dose 22 lamina generally will have athickness of 0.5 to 15 mils, usually 0.5 to 7.5 mils.

Exemplary solvents suitable for manufacturing wall 12 or coat 22 includeinert inorganic and organic solvents that do not adversely harm thewall, the lamina and the final dosage system. The solvents broadlyinclude a member selected from the group consisting of an alcohol,ketone, ester, ether, aliphatic hydrocarbon, halogenated solvents,cycloaliphatic solvents, aromatic heterocyclic, aqueous solvents, andmixtures thereof.

The dosage form 10 of the invention is manufactured by standardtechniques. For example, in one manufacture, the beneficial drug andother ingredients comprising the first layer facing the exit means areblended and pressed into a solid layer. The layer possesses dimensionsthat correspond to the internal dimensions of the area the layer is tooccupy in the dosage form and it also possesses dimensions correspondingto the second layer for forming a contacting arrangement therewith. Thedrug and other ingredients can be blended also with a solvent and mixedinto a solid or semisolid form by conventional methods, such asballmilling, calendering, stirring or rollmilling, and then pressed intoa preselected shape. Next, a layer of osmopolymer composition is placedin contact with the layer of drug in a like manner. The layering of thedrug formulation and the osmopolymer layer can be fabricated byconventional two-layer press techniques. The two contacted layers arefirst coated with an outer wall 12. The drug composition over outersurface of wall 12 can be applied by press coating, molding, spraying,dipping, and air suspension procedures. The air suspension and airtumbling procedures comprises in suspending and tumbling the pressed,contacting first and second layers in a current of air containing thedelayed-forming composition until the first and second layers aresurrounded by the wall composition.

In another manufacture, dosage form 10 is manufactured by the wetgranulation technique. In the wet granulation technique, the drug andthe ingredients comprising the first layer or drug composition, areblended using an organic solvent, such as denature anhydrous ethanol, asthe granulation fluid. The ingredients forming the first layer or drugcomposition are individually passed through a 40 mesh screen and thenthoroughly blended in a mixer. Next, other ingredients comprising thefirst layer can be dissolved in a portion of the granulation fluid, thesolvent described above. Then, the latter prepared wet blend is slowlyadded to the drug blend with continual mixing in the blender. Thegranulating fluid is added until a wet blend is produced, which wet massblend is then forced through a 20 mesh screen onto oven trays. The blendis dried for 18 to 24 hours at 24° C. to 35° C. in a forced air oven.The dried granules are then sized with a 20 mesh screen. Next, magnesiumstearate is added to the drug screened granulation, is then put intomilling jars and mixed on a jar mill for 10 minutes. The composition ispressed into a layer, for example, in a Manesty® press. The speed of thepress is set at 20 rpm and the maximum load set at 2 tons. The firstlayer is pressed against the composition forming the second layer andthe bilayer tablets are fed to the Kilian® dry Coata press andsurrounded with the drug-free coat followed by the exterior wall solventcoating.

Another manufacturing process that can be used for providing thecompartment-forming composition comprises blending the powderedingredients in a fluid bed granulator. After the powdered ingredientsare dry blended in the granulator, a granulating fluid, for example,poly(vinylpyrrolidone) in water, is sprayed onto the powders. The coatedpowders are then dried in the granulator. This process granulates allthe ingredients present therein while adding the granulating fluid.After the granules are dried, a lubricant such as stearic acid ormagnesium stearate is mixed into the granulation, using a V-blender. Thegranules are then pressed in the manner described above.

DESCRIPTION OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomemore apparent to those versed in the art in the light of the presentdisclosure, the drawing figures and the accompanying claims.

EXAMPLE 1

A dosage form for the controlled delivery of verapamil, comprisingadministering a dosage form at bedtime for releasing verapamil tocoincide with the early morning rise of blood pressure associated withhypertension and angina, is prepared as follows: first, 600 g ofverapamil hydrochloride, 305 g of poly(ethylene oxide) having amolecular weight of 300,000, and 40 g of sodium chloride (powder) werescreened through a 40 mesh stainless steel screen and blended with 50 gof polyvinylpyrrolidone, having a molecular weight of 38,000, for 15minutes in a blender to produce a homogenous mix. The granulating fluid,350 ml of anhydrous ethyl alcohol, is gradually added into the blendedingredients to produce a wet mass. The wet mass is dried at about 25°C., room temperature, for 16 hours. The dry granules are then passedthrough a 16 mesh stainless steel screen. Next, 5 g of magnesiumstearate is screened through an 80 mesh screen, and the screenedgranules added to the blended mix and all the ingredients blended in ablender for 2 minutes. This procedure provides the drug composition forproviding the drug layer of the reservoir.

The osmotic composition designed for preparing the push layer is made asfollows: first, 735 g of polyethylene oxide, having a 7,000,000molecular weight, 200 g of sodium chloride, 50 g ofhydroxypropylmethylcellulose, with a viscosity of 5 cps, and 10 g of redferric oxide, were screened through a 40 mesh screen and blended for 15minutes to produce a homogenous mix. Next, 700 ml of anhydrous ethylalcohol is gradually added to the blended ingredients during blendinguntil a wet granulation is obtained. The wet granulation is thenmanually screened through the 20 mesh screen and dried at 25° C. for 16hours. The dry granules are then passed through a 16 mesh screen. Then,5 g of magnesium stearate, which is prescreened through an 80 meshscreen, is then added to the granules and mixed in a blender for 2minutes. Next, a drug composition, pressed into a layer, is provided asfollows:

    ______________________________________                                        COMPONENTS    WT %    MG/DOSAGE FORM                                          ______________________________________                                                    DRUG COMPOSITION                                                  Verapamil HCL 60.0    198.0                                                   Polyox ® N-750                                                                          30.5    100.7                                                   PVP K29-32    5.0     16.5                                                    NaCl          4.0     13.2                                                    Mg Stearate   0.5     1.7                                                                 OSMOTIC COMPOSITION                                               303yox ®  73.5    80.9                                                    NaCl          20.0    22.0                                                    HPMC E-5      5.0     5.5                                                     Fe.sub.2 O.sub.3                                                                            1.0     1.1                                                     Mg Stearate   0.5     0.6                                                     ______________________________________                                    

The abbreviation "Polyox N-750" denotes polyethylene oxide of 300,000molecular weight, "HPMC E-5" denotes hydroxypropylmethylcellulose of11,200 molecular weight, "Polyox-303" indicates polyethylene oxide of7,000,000 molecular weight, and "PVP K29-32" denotespolyvinylpyrrolidone of 38,000 molecular weight.

Next, a wall forming composition comprising 55 wt % cellulose acetate,comprising a 39.8% acetyl content, 40 wt % hydroxypropylcellulose and 5wt % polyethylene glycol--3350 are dissolved in 80% acetone and 20%methanol was coated around the bilayer core, using a pan coater. A wallweighing 118 mg per dosage form is applied to provide the delayedrelease dosage form.

Two 30 mil orifices were drilled on the drug composition side of thedosage form. The dosage form exhibited an in vitro 1.5 hours drug-freeinterval followed by delivering the verapamil drug at a controlledrelease rate of 20 mg/hour for 8 hours.

EXAMPLE 2

The procedure of Example 1 is followed in this example, with allmanufacturing procedures and compositions as previously described,except that, in this example, the osmotic push composition is asfollows:

    ______________________________________                                                    OSMOTIC COMPOSITION                                               COMPONENTS    WT %    MG/DOSAGE FORM                                          ______________________________________                                        303yox ®  73.5    147.0                                                   NaCl          20.0    40.0                                                    HPMC E-5      5.0     10.0                                                    Fe.sub.2 O.sub.3                                                                            1.0     2.0                                                     Mg Stearate   0.5     1.0                                                     ______________________________________                                    

Three 30 mil orifices were drilled on the drug side of each dosage form.The dosage form exhibited a 1 hour drug-free interval followed bydelivering 40 mg/hour of verapamil over 5 hours.

EXAMPLE 3

An osmotic dosage form for the controlled and continuous release of acalcium channel blocker drug as exemplified by verapamil after aprogrammed delay of about 2 hours, was made as follows: first, 5,400 gof verapamil hydrochloride, 2,745 g of poly(ethylene oxide) of 300,000molecular weight, 225 g of polyvinylpyrrolidone of 38,500 molecularweight and 360 g of sodium chloride were passed through a 16 meshscreen. Next, the screened excipients were introduced into the fluid bedgranulator for 30 minutes and preheated to 35° C. A granulation solutionconsisting of 225 g of polyvinylpyrrolidone of 40,000 molecular weightdissolved in 2,588 g of distilled water was sprayed onto the fluidizedpowders in the granulator. Then, 45 g of magnesium stearate, which isprescreened through an 80 mesh screen, were added to the granules in amixer and the ingredients blended for 3 minutes.

An osmotic push composition was prepared in a similar manner. Thecomposition comprised 117,600 g of polyethylene oxide with a 7,500,000molecular weight, 32,000 g of sodium chloride, 3,200 g ofhydroxypropylmethylcellulose of 11,200 molecular weight, and 1,600 g offerric oxide were screened through a 17 mesh screen. Next, the screenedingredients were introduced into a fluid bed granulator for 30 minutespreheated to 35° C. A granulating fluid consisting of 4,800 g ofhydroxypropylmethylcellulose, of 5 cps viscosity dissolved into 55,200 gof distilled water, was sprayed onto the fluidized ingredients.

Next, a bilayer core comprising a drug composition and a pushcomposition was prepared in a Manesty® Tablet Press. The bilayer coreswere surrounded with a cellulose acetate, hydroxypropylcellulose walland an orifice drilled through the wall is described in Example 1. Thedosage form after a 2 hour drug delay period delivers 21 mg/hour of drugover a prolonged period of time.

EXAMPLE 4

The procedures described in the above examples are repeated in thisexample, with all the conditions as previously set forth, except that inthis example, the drug is a calcium channel blocking drug selected fromthe group consisting of nifedipine, isradipine, nilvadipine,flunarizine, nimodipine, diltiazem, nicardipine, nitredipine,nisoldipine, felodipine, amlodipine, cinnarizine and fendiline.

EXAMPLE 5

The procedure described in the above examples is repeated in thisexample, with all the conditions as previously set forth, except that,in this example, the drug is an angiotensin converting enzyme inhibitorselected from the group consisting of alacipril, benazepril, cialzapril,captopril, delapril, enalapril, fosinopril, lisinopril, moveltipril,perindopril, quinapril, ramipril, spirapril, and zofenopril.

EXAMPLE 6

The dosage form prepared according to the above examples, wherein thedosage form is an osmotic delivery device comprising a caplet shape foreasy oral drug administration.

EXAMPLE 7

In this example, the rate of hydration of (1) a wall compositioncomprising 60 wt % cellulose acetate consisting of 39.8% acetyl content,35 wt % polyvinylpyrrolidone of 38,000 molecular weight and 5 wt %polyethylene glycol 3350 is compared with the rate of hydration of (2) awall composition comprising 60 wt % cellulose acetate comprising a 39.8%acetyl content, 35 wt % hydroxypropylcellulose of 38,000 molecularweight and 5 wt % polyethylene glycol 3350. The composition (1)comprising polyvinylpyrrolidone hydrates quickly and lets fluid passinto the dosage form, while composition (2) comprisinghydroxypropylcellulose hydrates very slowly and substantially delays thepassage of fluid into the dosage form for 2 hours. The composition (2)operates with synergetic effect with the drug composition comprising apolymer of 250,000 to 350,000 molecular weight. Polymers of lowermolecular weight are substantially devoid of delay, which the polymerused by this invention exhibits a long delay prior to converting to adrug delivery phase.

EXAMPLE 8

In this example, the above procedures are followed, with the addedmanufacture a hydroxypropylcellulose is interposed between the inside ofthe semipermeable wall and around the first or drug composition and thesecond or push composition. The interposed layer is about 6 mm thick andit slows or delays the rate of fluid imbibition into the first andsecond composition. The layer is applied as a dry composition by presscoating the layer in the interposed position.

EXAMPLE 9

The procedures of the above examples are repeated in this example, withthe added embodiment comprising the wall, which is coated on its outersurface with an instant dose of verapamil hydrochloride.

METHOD OF PRACTICING THE INVENTION

A presently preferred embodiment of the invention pertains to a methodfor delivering a drug to a patient during a circadian cycle comprisingan active phase and a less active phase, wherein the method comprises:(A) orally admitting into the patient a dosage form comprising means fordelivering a drug during the active phase and means for providing adrug-free interval during the less active phase. The method comprises:(B) admitting into the patient a dosage form comprising: (1) a wall thatsurrounds and forms an internal compartment, said wall comprising acomposition for slowing the fluid flux through the wall; (2) a drugcomposition in the compartment, said composition comprising means fordelaying the delivery of drug from the dosage form; (3) a pushcomposition in the compartment for pushing the drug composition from thedosage form; (4) an orifice in the dosage form for delivering the drugfrom the dosage form; (B) imbibing fluid through the wall at a ratedetermined by the osmotic pressure gradient across the wall, therebycausing the drug composition to slowly form a dispensable compositionand the push composition to absorb fluid and push the dispensable drugcomposition from the dosage form; and, (C) delivering the drug after adrug-free interval to the patient. The invention provides also aninstant dose of drug by delivering a drug from an external instantrelease drug coat. In this delivery pattern, the instant release isfollowed by a drug-free interval. The method of the invention for thetreatment of hypertension and angina provides a drug-free interval whena patient is less active, that is, at rest or when asleep and theinvention provides drug during the rising or waking hours mainly duringthe time when activity reaches a maximum during the daytime hours.

The novel osmotic dosage form of this invention uses dual means for theattainment of precise release rate of drugs that are difficult todeliver in the environment of use, while simultaneously maintaining theintegrity and the character of the system. While there has beendescribed and pointed out features and advantages of the invention, asapplied to the presently preferred embodiments, those skilled in thedispensing art will appreciate that various modifications, changes,additions, and omissions in the system illustrated and described can bemade without departing from the spirit of the invention.

We claim:
 1. A dosage form for the delayed-delivery of a drug, whereinthe dosage form comprises:(a) a first composition comprising 0.05nanograms to 1.5 grams of the drug verapamil and 20 wt % to 50 wt % of apoly(ethylene oxide) present in the first composition, saidpoly(ethylene oxide) comprising means for changing from a nondispensableviscosity to a dispensable viscosity when contacted by fluid that entersthe dosage form; (B) a second composition comprising a polymericcomposition that imbibes fluid and expands, whereby the secondcomposition pushes the first composition from the dosage form; (C) awall that surrounds the first and second compositions, said wallpermeable to the passage of fluid present in the environment of use andcomprises 35 wt % to 55 wt % of a polymeric composition that hydratesslowly when contacted by fluid that enters the wall; (D) at least oneexit means in the wall for delivering the drug from the dosage form;and, wherein the dosage form is characterized by: (E) a delayed-druginterval for delivering verapamil up to 4.5 hours provided by (A), (B)and (C) operating in combination as a unit to provide the delayed-druginterval.
 2. The dosage form for the delayed-delivery of a drugaccording to claim 1, wherein the drug verapamil is replaced by adifferent drug selected from the group consisting of a calcium channelblocker and its pharmaceutically acceptable derivatives.
 3. The dosageform for the delayed-delivery of a drug according to claim 1, whereinthe drug verapamil is replaced by a member selected from the groupconsisting of nifedipine, nilvadipine, flunarizine, nimodipine,diltiazem, nicardipine, nitredipine, nisoldipine, felodipine,amlodipine, cinnarizine, and fendiline.
 4. The dosage form for thedelayed-delivery of a drug according to claim 1, wherein the drugverapamil is a member selected from the group consisting of verapamiland its pharmaceutically acceptable salts.
 5. The dosage form for thedelayed-delivery of a drug according to claim 1, wherein the drugverapamil is replaced by a member selected from the group consisting oframipril, fosinopril, altiopril, benazepril, libenzapril, alacepril,cialzapril, cilazaprilat, perindopril, zofenopril, enalapril,lisinopril, imidapril, spriapril, rentiapril, captopril, delapril,olindapril, indalapril and quinapril.
 6. The dosage form foradministering the drug according to claim 1, wherein the orifice is apore-orifice.
 7. A method for administering the drug verapamil to thegastrointestinal tract of a patient in need of verapamil therapy, whichmethod comprises:(A) admitting a dosage form into the gastrointestinaltract of the patient, said dosage form comprising:(1) a wall thatsurrounds and defines the compartment, said wall comprising 35 wt % to55 wt % of a hydroxypropylcellulose and a member selected from the groupconsisting of cellulose acetate, cellulose diacetate, and cellulosetriacetate; (2) a drug composition in the compartment, said compartmentcomprising a therapeutically effective dose of 0.05 nanograms to 1.5grams of the verapamil drug and 20 wt % to 50 wt % of a poly(ethyleneoxide); (3) a push composition in the compartment that imbibes fluidinto the compartment, expands and pushes the drug composition from thedosage form, said push composition comprising a poly(ethylene oxide)which is different than the poly(ethylene oxide) in the drugcomposition; and (4) a passageway in the dosage form for delivering thedrug composition from the dosage form; and, wherein the dosage form inthe gastrointestinal tract; (B) changes from a delayed drug-free stateover 30 minutes to 4.5 hours to a dispensable drug-delivery state; and,(C) administering the drug verapamil to the gastrointestinal tract ofthe patient by the push composition displacing the drug from the dosageform.
 8. The method for administering the drug verapamil to thegastrointestinal tract of a patient according to claim 7, wherein aninstant dose of verapamil is administered from an external coat incontact with the wall.
 9. The method for administering the drugverapamil to the gastrointestinal tract of a patient according to claim7, wherein the dosage form delivers verapamil after a 2 hour drug-freeinterval.
 10. The method for administering the drug verapamil to thegastrointestinal tract of a patient according to claim 7, wherein thedosage form is administered at bedtime.
 11. The method for administeringthe drug verapamil to the gastrointestinal tract of a patient accordingto claim 7, wherein the dosage form administers verapamil during thenight hours.